Increasing the Potency of CD-34-DC Vaccines

提高 CD-34-DC 疫苗的效力

• 批准号: 7122671
• 负责人: Jacques F Banchereau
• 金额: $ 11.2万
• 依托单位: BAYLOR RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-03-01 至 2009-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7122671
• 关键词: CD34 molecule; Langerhans' cell; MHC class I antigen; MHC class II antigen; biotechnology; clinical trial phase I; clinical trial phase II; cytotoxic T lymphocyte; dendritic cells; flow cytometry; helper T lymphocyte; human subject; human therapy evaluation; immune response; interferon alpha; melanoma; myeloid stem cell; neoplasm /cancer immunology; neoplasm /cancer vaccine; neoplastic cell; patient oriented research; tissue /cell culture; tumor antigens; vaccine development; vaccine evaluation

Using melanoma peptide loaded CD34-DCs, a composite vaccine composed of Langerhans cells and Interstitial DCs, we have demonstrated that DC vaccines can induce tumor-specific immunity, as well as some clinical responses. Two major questions arise: 1) Why is the composite vaccine efficient? and 2) How can the therapeutic immunogenicity of DC vaccines be improved? With this in mind, AIM 1 will test the hypothesis that composite DC vaccines loaded with killed allogeneic melanoma cells will have superior therapeutic efficacy, because of i) presentation of multiple tumor antigen epitopes to both CD4 and CDS T cells, and ii) strong allogeneic help. This will be a Phase l/ll single arm clinical trial which Primary Objective is induction of melanoma antigen-specific CD8+T cells and Secondary Objective is induction of objective clinical responses. The trial is powered based on the rate of induction of melanoma-specific CD8+T cell immunity and will accrue up to 51 metastatic melanoma patients. Interim analyses will be conducted after 9 and 24 patients are enrolled to assess toxicity and immunogenicity. Immune responses will be assessed using EPIMAX strategy. The 2 main quantitative assays involve melanoma antigen-specific IFN-gamma release (effector memory cells) and cell proliferation (CFSE and flow cytometry; recall memory) by T cells in short term PBMCs cultures with selected melanoma antigen-peptides. AIM2 will assess the helper functions of melanoma antigen-specific CD4+T cells in patients vaccinated with composite DCs loaded with killed allogeneic melanoma cells. We want to establish an assay to measure the ability of melanoma-antigen specific CD4+T cells to prime melanoma-antigen specific CD8+T cells. AIM 3 will determine which DC subset present in composite DCs vaccines primes melanoma antigen-specific CD4+T cells that help CD8+T cells. AIM 4 will test the hypothesis that further activation of myeloid DC vaccines, indirectly through the activation of pDCs or exposure to IFN-a, will increase their efficacy in vitro.

使用肽肽加载的CD34-DCS，一种由Langerhans细胞组成的复合疫苗和 间质直流，我们已经证明了直流疫苗可以诱导肿瘤特异性免疫力，并且 一些临床反应。出现了两个主要问题：1）为什么复合疫苗有效？ 2）如何 可以改善直流疫苗的治疗性免疫原性吗？考虑到这一点，AIM 1将测试 假设的假设是，装有杀死的同种异体黑色素瘤细胞的复合DC疫苗将具有优越性的 治疗功效，因为i）表现出多种肿瘤抗原表位为CD4和CDS T 细胞，ii）强大的同种异体帮助。这将是一项L/LL单臂临床试验，主要目标 是诱导黑色素瘤抗原特异性CD8+T细胞，次要目标是诱导目的 临床反应。该试验是根据黑色素瘤特异性CD8+T细胞的诱导速率驱动的 免疫力，最多可产生51例转移性黑色素瘤患者。临时分析将在9后进行 24例患者被招募以评估毒性和免疫原性。免疫反应将评估 使用Epimax策略。 2个主要定量测定涉及黑色素瘤特异性IFN-gamma T细胞中的释放（效应器记忆细胞）和细胞增殖（CFSE和流式细胞术；回忆记忆） 短期PBMC培养物，具有选定的黑色素瘤抗原肽。 AIM2将评估助手功能 用载有杀死的复合材料DC接种的患者中的黑色素瘤抗原特异性CD4+T细胞 同种异体黑色素瘤细胞。我们想建立一个测量来测量黑色素瘤抗原的能力 特定的CD4+T细胞针对特异性黑色素瘤特异性CD8+T细胞。 AIM 3将确定哪个DC 复合DCS疫苗中存在的子集素瘤黑色素瘤抗原特异性CD4+T细胞有助于CD8+T 细胞。 AIM 4将检验以下假设：髓样直流疫苗的进一步激活，间接地通过 PDC的激活或暴露于IFN-A，将在体外提高其功效。